This proposal seeks to continue the development of a glucose monitoring system capable of continuous monitoring of blood glucose in diabetic patients. The basis for glucose sensing is an enzyme microelectrode (o.d. 250 microns) which is implanted subcutaneously and which generates a current proportional to the glucose concentration in the surrounding tissue. It has been shown that the sensor can provide a reliable estimate of blood glucose as determined by experiments in rats and in humans. The sensor is connected to a wearable electronic control unit (ECU) (weight 200g) which converts the current into a blood glucose value displayed on a built-in LCD. The success of the system depends on stable, reproducible sensor behavior and the ability of the ECU to process and store the resulting signal. In the present proposal emphasis will be placed on examining carefully several important issues related to continuous monitoring as part of the treatment of diabetes through insulin therapy. These include determining rigorously the optimal site of implantation, demonstrating that an abdominal site can be used as well as the forearm, the protocol for automatic in-vivo calibration of the sensor, and the effect of exercise on sensor performance. Continuous monitoring will also be used to detect and observe nocturnal hypoglycemia, and to develop a hypoglycemia alarm. The sensor is intended to be implanted for 4-7 days, so the evaluation of the sensor and the ECU over this period of time is essential. Improvements in both the sensor the ECU are suggested which will increase the reliability and the length of time they may be used. Accordingly pre-clinical trials will be conducted on both normal and diabetic subjects. These studies will be of paramount importance in providing statistical data necessary to perform power analysis for the design of large scale clinical trials, which are beyond the scope of the present program. Sensor performance is first evaluated in rats prior to human use. Our expertise in sensor design will be used to measure ECF glucose fluctuations in the brain under varying glycemia levels. This may have implications in the understanding of diabetes and its treatment.